Inhibition of urokinase plasminogen activator “uPA” activity alters ethanol consumption and conditioned place preference in mice

Abstract

Urokinase plasminogen activator, uPA, is a serine protease implicated in addiction to drugs of abuse. Using its specific inhibitor, B428, we and others have characterized the role of uPA in the rewarding properties of psychostimulants, including cocaine and amphetamine, but none have examined the role of uPA in ethanol use disorders. Therefore, in the current study, we extended our observations to the role of uPA in ethanol consumption and ethanol-induced conditioned place preference. The general aim of the present series of experiments was to investigate the effects of the administration of the B428 on voluntary alcohol intake and ethanol conditioned reward. A two-bottle choice, unlimited-access paradigm was used to compare ethanol intake between vehicle- and 3, 10, and 30 mg/kg B428-administered mice. For this purpose, the mice were presented with an ethanol solution (2.5%–20%) and water, at each concentration for 4 days, and their consumption was measured daily. Consumption of saccharin and quinine solutions was also measured. Systemic administration of B428 dose-dependently decreased ethanol intake and preference. Additionally, B428 mice did not differ from vehicle mice in their intake of graded solutions of tastants, suggesting that the uPA inhibition did not alter taste function. Also, ethanol metabolism was not affected following B428 injection. More importantly, 1.5 g/kg ethanol-induced conditioned place preference acquisition was blocked following B428 administration. Taken together, our results are the first to implicate uPA inhibition in the regulation of ethanol consumption and preference, and suggest that uPA may be considered as a possible therapeutic drug target for alcoholism and abstinence.

Keywords:

• B428
• CPP
• two-bottle choice

Acknowledgments

This work was supported by grants from the United Arab Emirates University and the National Research foundation.

The authors are grateful to Dr Bruce A Littlefield of Eisai, Inc., Andover, MA, USA, for providing B428. The authors would like to acknowledge Mr Mohamed Elwasila and Mr Mohamed Shafiullah for their technical assistance, and Dr Mahmoud Hag Ali, of the Central Animal Facility, for his advice on veterinary care.

Author contributions

AB was responsible for the study concept and design. EA, SA, MA, and AB contributed to the acquisition of animal data. AB performed the data analysis, and EA, SA, and MA helped in the interpretation of findings. EA and AB drafted the manuscript. All the authors provided critical revision of the manuscript for important intellectual content, reviewed content, and approved the final version for publication.

Disclosure

The authors report no conflicts of interest in this work.